WO2015050388A1 - Pharmaceutical composition for preventing or treating ischemic brain disorders, containing fimasartan - Google Patents

Pharmaceutical composition for preventing or treating ischemic brain disorders, containing fimasartan Download PDF

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WO2015050388A1
WO2015050388A1 PCT/KR2014/009296 KR2014009296W WO2015050388A1 WO 2015050388 A1 WO2015050388 A1 WO 2015050388A1 KR 2014009296 W KR2014009296 W KR 2014009296W WO 2015050388 A1 WO2015050388 A1 WO 2015050388A1
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fimasartan
ischemic brain
preventing
salt
brain disease
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PCT/KR2014/009296
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French (fr)
Korean (ko)
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윤병우
김치경
지용하
김형국
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보령제약 주식회사
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to a pharmaceutical composition for preventing or treating ischemic brain disease, including fimasartan or a salt thereof.
  • ischemic stroke which is caused by an ischemic state of the brain tissue due to a decrease or blocking of blood supply to the brain tissue
  • hemorrhagic stroke which causes blood vessels to bleed and cause bleeding from the brain tissue.
  • cerebral ischemia is a serious disease that accounts for about 80% of all stroke patients.
  • the cells in the core region of the cerebral ischemia caused by blockage or reduction of oxygen supply due to a blood circulation disorder begin to malfunction within a few seconds to several minutes and eventually become irreversible damage.
  • cells in the penumbra region are impaired in metabolic function, they can block irreversible cell damage if treated properly and quickly.
  • Stroke agents currently in use in clinical trials include thrombolytic agents such as tissue plasminogen activators (TPA) or urokinase, and drugs of various mechanisms, including platelet inhibitors, anticoagulants, cerebrovascular agents, Ca2 + channel blockers, and brain edema inhibitors.
  • TPA tissue plasminogen activators
  • drugs of various mechanisms including platelet inhibitors, anticoagulants, cerebrovascular agents, Ca2 + channel blockers, and brain edema inhibitors.
  • these drugs have a weak effect when the treatment period is delayed, they do not effectively block the progression of cerebral ischemia due to acute cerebral ischemia, and are known to have side effects such as nonspecific bleeding, fibrinogen lysis, and acute reoccurrence (Scheinberg P. et al. , Stroke 25: 1290-1295, 1994).
  • angiotensin is an important substance causing high blood pressure, and there have been attempts to suppress stroke by controlling hypertension, a powerful risk factor of stroke, through angiotensin receptor inhibitors.
  • angiotensin receptor inhibitors there are no reports on the treatment of brain diseases that do not depend on the blood pressure-lowering effects of angiotensin receptor inhibitors.
  • Fimasartan is 2-n-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl ] Pyrimidin-4 (3H) -one ⁇ 2-n-Butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] pyrimidin -4 (3H) -one ⁇ , which has the following structural formula and is known as an antihypertensive agent of the Angiotensin II Receptor Blocker (ARB) family.
  • ARB Angiotensin II Receptor Blocker
  • Fimasartan is currently approved for drug use under the product name of KANARB, etc., and is known to have a very superior blood pressure lowering effect in patients with mild to severe hypertension. However, there is no known new use of pimasartan other than the hypotensive effect.
  • the present inventors have completed the present invention as a result of recognizing the problem of the existing ischemic brain disease treatment agent and researching to develop a new ischemic brain disease treatment use of the existing drug.
  • angiotensin receptor inhibitor pimasartan exhibited a previously known ischemic brain disease prevention or treatment effect and completed the present invention.
  • an object of the present invention is to provide a new pharmaceutical composition capable of preventing or treating ischemic brain disease through anti-inflammatory action in the damaged brain area without affecting blood pressure.
  • the present invention provides a pharmaceutical composition for preventing or treating ischemic brain disease, including Fimasartan or a salt thereof.
  • the fimasartan salt is selected from the group consisting of fimasartan potassium salt, hydrochloride, calcium salt, sulfate, adipate salt, camsylate salt and besylate salt, ischemic brain disease prevention or treatment It provides a pharmaceutical composition.
  • the present invention is characterized in that the ischemic brain disease is selected from the group consisting of stroke, stroke, cerebral hemorrhage, cerebral infarction, head injury, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, lethargy and shock brain injury.
  • the ischemic brain disease is selected from the group consisting of stroke, stroke, cerebral hemorrhage, cerebral infarction, head injury, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, lethargy and shock brain injury.
  • a prophylactic or therapeutic pharmaceutical composition is provided.
  • the present invention also provides a pharmaceutical composition for preventing or treating ischemic brain disease, wherein the ischemic brain disease is stroke or cerebral infarction.
  • the present invention also provides a pharmaceutical composition for preventing or treating ischemic brain disease, wherein the fimasartan has an anti-inflammatory action.
  • the present invention provides a pharmaceutical composition for preventing or treating ischemic brain disease, which is an oral or injectable preparation.
  • the present invention also provides a pharmaceutical composition for preventing or treating ischemic brain disease, comprising 1 to 240 mg of fimasartan.
  • Fimasartan of the present invention has an excellent effect in preventing or treating ischemic brain disease by inhibiting cerebral infarction and inhibiting ischemic cell death through anti-inflammatory action at the site of brain injury.
  • FIG. 1 is a diagram showing a schematic diagram of an experiment for confirming the effect of inhibiting ischemic brain disease according to the administration of fimasartan.
  • Figure 2 is a diagram showing the manufacturing process of the cerebral infarction rat model.
  • Figure 3 is a diagram showing the result of confirming the volume of cerebral infarction through the needle stain method 7 days after induction of cerebral infarction.
  • Figure 4 is a diagram showing the results of comparing the size of the cerebral infarction site of the control group and low dose pimasartan 0.5mg / kg administration group.
  • Figure 5 is a diagram showing the results of analyzing the ischemic cell density killed by the TUNEL assay.
  • FIG. 6 is a diagram showing the results of confirming the blood pressure change in the 1 mg / kg, 3 mg / kg administration group Fimasartan.
  • Figure 7 shows the results of confirming the blood pressure change in the low-dose pimasartan 0.5mg / kg administration group.
  • FIG. 8 is a diagram showing the results of confirming the presence of inflammatory cells in the cerebral infarction area using the Ox6 staining method.
  • FIG. 9 is a diagram showing the results of Western blot changes in the expression level of pSTAT3 in the group administered 0.5 mg / kg fimasartan.
  • Figure 10 is a diagram showing the results confirmed by Western blot changes in the expression of iKB degradation and COX2 protein in the group administered 0.5mg / kg fimasartan.
  • 11 is a schematic diagram showing the mechanism of anti-inflammatory effect of fimasartan.
  • FIG. 12 is a diagram showing the results of analyzing the behavioral changes in the behavioral behavior in the experimental group administered with pimasartan.
  • FIG. 13 is a diagram showing the results of measuring the survival rate of the pimasartan-administered group and the control group during the 28 days of infarction.
  • the present invention provides a pharmaceutical composition for preventing or treating ischemic brain disease comprising Fimasartan or a salt thereof.
  • Fimasartan of the present invention has an excellent effect in preventing or treating ischemic brain disease by inhibiting cerebral infarction and inhibiting ischemic cell death through anti-inflammatory action at the site of brain injury. Therefore, in the selection of antihypertensive agents in patients at high risk of cerebral infarction, when selecting Pimasaltan, the blood pressure problem may be solved, and cerebral infarction may be effectively prevented or treated.
  • the fimasartan and pharmaceutically acceptable salts thereof, solvates thereof or hydrates thereof in the present invention may be crystalline or amorphous, and the present invention includes their crystalline and / or amorphous forms.
  • pharmaceutically acceptable salts generally mean inorganic acid salts, organic acid salts, and metal salts used by pharmaceutical manufacturers to prepare medicines.
  • organic acid hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, and the like may be used.
  • Organic acid includes citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, benzoic acid, gluconic acid, glycolic acid, succinic acid, 4-morpholine Ethanesulfonic acid, camphorsulfonic acid, 4-nitrobenzenesulfonic acid, hydroxy-O-sulfonic acid, 4-toluenesulfonic acid, kalucturonic acid, emboic acid, glutamic acid, aspartic acid, adipate salt, camsylate salt or besylate salt
  • metal includes sodium, potassium, calcium, magnesium, and the like.
  • the fimasartan salt is preferably pimasartan potassium salt, hydrochloride, calcium salt, sulfate, adipate salt, camsylate salt or besylate salt. These are commercially available and can be manufactured by known methods (for example, Korean Patent Registration Nos. 0354654 and 0521980, etc.).
  • the solvent in the "solvate” means a conventional organic solvent used to prepare an organic compound, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1 Acetates, acetone, acetic acid, anisole, tetrahydrofuran, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, dimethyl sulfoxide, pentane, heptane, and the like.
  • the solvates of the present invention are not limited.
  • hydrate and “solvate” may be contained in a 0.25 to 10 molar ratio with respect to 1 mole of fimasaltan, for example 0.5 mole, 1 mole, 1.5 mole, 2 mole, 2.5 mole, 3 mole, 5 moles, etc., but the present invention is not limited thereto.
  • Fimasartan or a salt thereof of the present invention is excellent in preventing or treating ischemic brain disease, and the ischemic brain disease is stroke, stroke, cerebral hemorrhage, cerebral infarction, head injury, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, lethargy and It is preferably selected from the group consisting of shock brain injury, more preferably stroke or cerebral infarction.
  • Fimasartan or a salt thereof of the present invention is a substance known as an angiotensin receptor inhibitor, and has an effect of preventing or treating ischemic brain disease through anti-inflammatory action irrelevant to blood pressure control.
  • the fimasartan or salt thereof exhibits anti-inflammatory action at the site of cerebral infarction, thereby inhibiting the expression of inflammatory factors and inhibiting the influx of inflammatory cells, thereby preventing ischemic cell death and reducing the site of brain injury. Effect.
  • compositions of the present invention may be administered in various formulations, oral and parenteral, in actual clinical administration.
  • it may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants commonly used.
  • the pharmaceutical composition of the present invention is preferably an oral or injectable preparation.
  • Solid preparations for oral administration include tablets, pills, powders, granules, and capsules, and the like, which may be used in the pharmaceutical compositions of the present invention at least one excipient such as starch, calcium carbonate, sucrose, It is prepared by mixing lactose and gelatin.
  • excipients such as starch, calcium carbonate, sucrose, It is prepared by mixing lactose and gelatin.
  • lubricants such as magnesium, styrene, and talc may also be used.
  • Liquid preparations for oral administration include suspensions, solutions, emulsions and syrups, and may include various excipients such as wetting agents, sweeteners, fragrances and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories.
  • non-aqueous solvent and the suspension solvent propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used.
  • base of the suppository witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used.
  • the pharmaceutical composition of the present invention may be administered by subcutaneous injection, intravenous injection or intramuscular injection during parenteral administration.
  • the pharmaceutical composition of the present invention may be formulated by adding a pharmaceutically acceptable carrier, and the formulation may be referred to Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA.
  • the pharmaceutically acceptable carrier refers to those commonly used in preparing pharmaceutical compositions to those skilled in the art.
  • lactose dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pi Ralidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • Pharmaceutically acceptable carriers also include diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like.
  • the present invention is not limited to the above-listed pharmaceutically acceptable carriers and the like, which are merely exemplary.
  • fimasartan contained in the pharmaceutical composition depends on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected in some cases.
  • fimasartan may be orally administered at a dose of about 1 to 240 mg, preferably 30 to 180 mg per day, based on a normal adult weighing about 60 kg, and the application may be applied once or several times a day. .
  • the pharmaceutical composition may include about 1 mg to 240 mg of fimasartan or a salt thereof, and preferably about 30 to 180 mg.
  • the pharmaceutical composition can be applied to mammals such as humans by various routes, for example by oral, intravenous, intramuscular, or subcutaneous injection.
  • composition of the present invention may contain at least one active ingredient exhibiting a prophylactic or therapeutic effect in addition to fimasartan.
  • composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, drug treatment and biological response modifiers for the improvement, alleviation, treatment or prevention of ischemic brain disease.
  • Fimasartan or the salt thereof of the present invention may play a role of protecting the brain from ischemic brain disease regardless of the mechanism of lowering blood pressure through anti-inflammatory action, and is toxic even when administered at a low dose for a long time as compared to conventional use. Without anti-inflammatory action and cerebral infarction effect is very good, the present invention provides the use of a new composition comprising fimasartan for the prevention or treatment of ischemic brain disease.
  • the present invention also provides the use of Fimasartan or a salt thereof for preventing or treating ischemic brain disease.
  • the present invention also provides a method for preventing or treating ischemic brain disease by administering a composition comprising Fimasartan or a salt thereof.
  • composition may be administered to a subject, and when administered to the subject, may be administered in an amount effective to prevent or treat ischemic brain disease.
  • the subject refers to an animal, and is typically a mammal that may have a beneficial effect with treatment with fimasartan or a salt thereof of the present invention.
  • Preferred examples of such subjects include primates, such as humans.
  • Such subjects also include all subjects with or at risk of having ischemic brain disease.
  • Such effective amount means an amount that provides a desired outcome or objective or subjective benefit in a subject, in single or multiple doses, alone or in combination with one or more other therapeutic agents, and the like.
  • the present invention also provides the use of Fimasartan or a salt thereof for the manufacture of a medicament for preventing or treating ischemic brain disease.
  • the ischemic brain disease is preferably selected from the group consisting of stroke, stroke, cerebral hemorrhage, cerebral infarction, head injury, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, lethargy and shock brain injury, more preferably stroke Or cerebral infarction.
  • fimasartan or salt thereof of the present invention may be selected from the group consisting of fimasartan potassium salt, hydrochloride, calcium salt, sulfate, adipate salt, camsylate salt and besylate salt.
  • Fimasartan or a salt thereof of the present invention is a substance known as an angiotensin receptor inhibitor, and has an effect of preventing or treating ischemic brain disease through anti-inflammatory action irrelevant to blood pressure control.
  • the fimasartan or a salt thereof may be about 1mg to 240mg, preferably about 30 to 180mg.
  • Sprague-Dawley rats were used as cerebral infarction model and all rats were confirmed to have normal blood pressure.
  • Sprague-Dawley rats received oral fimasartan at a low dose of 0.5 mg / kg, normal dose of 1 mg / kg, and 3 mg / kg once a week, four weeks before cerebral infarction, and the final volume and the same amount of PBS in the experimental group.
  • the administered group was used as a control.
  • a model of obstruction-reperfusion cerebral infarction via occlusion-reperfusion injury for 60 minutes was then made in the left-middle Cerebral Artery (MCA).
  • Occlusion of the left-middle cerebral artery was performed using a modified Longa technique (Zea Longa E, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989; 20: 84-91.).
  • FIG. 2 The preparation of the cerebral infarction rat model is shown in FIG. 2.
  • the brain was induced in the rat 7 days after the brain was extracted from the rat and the size change of the cerebral infarction was measured.
  • the area where cerebral infarction occurred was identified by using a Nisle staining method to stain neural tissue with basic aniline dye, and the size of cerebral infarction was specifically measured through image analysis.
  • the cerebral infarction volume was measured 7 days after the induction of cerebral infarction. As a result, it was confirmed that the site where cerebral infarction occurred was reduced in both the low dose and the general dose fimasartan-administered group. In particular, the test group the administration of castor oil saltan 0.5mg / kg with a low dose of 46.2mm 3 was confirmed that considerably as compared to 153.4mm 3 in the PBS treated control group is reduced cerebral infarction volume occurs.
  • Ischemic cell death was analyzed by TUNEL assay 7 days after inducing cerebral infarction in the rat according to the method of 1.1.
  • TUNEL positive cells As shown in Figure 5, it was confirmed that the density of TUNEL positive cells showing dead ischemic cells was significantly reduced in the Pimasaltan administration group. TUNEL positive cells had a density of 1302.5 / mm 2 and 553 / mm 2 in the control group in the low dose Fimasartan 0.5mg / kg. That is, the administration of fimasartan was found to suppress cerebral infarction by inhibiting the death of cells caused by ischemia.
  • pimasartan angiotensin receptor, prevents cell death due to ischemia and has new medicinal uses that can suppress cerebral infarction.
  • Example 1 It was further confirmed whether the effect of inhibiting cerebral infarction of the fimasartan confirmed in Example 1 was indicated by the blood pressure control of the fimasartan. This is to determine whether the anti-infarction effect of pimasartan is exhibited by blood pressure control, which is a risk factor for inducing cerebral infarction.
  • blood pressure control which is a risk factor for inducing cerebral infarction.
  • the blood pressure changes before and after infarction-induced cerebral infarction were measured in the rats of 1.1. Blood pressure was measured from 4 weeks before infarction to 7 days after infarction.
  • the rat model administered the normal dose of pimasartan 1mg / kg, 3mg / kg showed a significant mean blood pressure decrease in both systolic and diastolic compared to the control group.
  • the rats treated with 0.5 mg / kg of low dose of pimasartan showed no significant blood pressure reduction for 4 weeks before and 7 days after induction of cerebral infarction. Showed.
  • Example 1 In the 0.5 mg / kg pimasartan-administered group identified as the dose showing the best cerebral infarction effect in Example 1, the density of inflammatory cells at the periphery of cerebral infarction was measured by immunohistochemistry and 7 days after the infarction. The mechanism of inhibition of cerebral infarction was analyzed by confirming using.
  • Ox6 is a specific marker of microphage and microglia and can determine the degree of inflammation by measuring the density of Ox6 positive cells.
  • Ox6 positive cell density was significantly decreased in the region around the cerebral infarction of the pimasartan 0.5 mg / kg administration group compared with the control group. More specifically, the median density of Ox6 positive cells in the experimental group administered 0.5 mg / kg of low dose fimasartan was 157 / mm 2 and 654 / mm 2 in the control group.
  • the control group exhibited 6 behavioral patterns due to neurological injury after cerebral infarction, but the change in behavioral pattern was lower to 4 points in the experimental group administered with pimasartan, and 14 days The difference between the two points was shown in the tea, and the changes in functional behavior due to cerebral infarction were also alleviated. That is, when administering fimasartan, nerve damage due to cerebral infarction is alleviated, and thus, physical paralysis due to nerve damage may be alleviated.
  • the control group that did not receive fimasartan showed a survival rate of less than half after 28 days of infarction, whereas the experimental group that received fimasartan showed a high survival rate of 0.8 or more after 28 days.
  • the experimental group administered with pimasartan can effectively lower the death rate due to brain injury by suppressing cerebral infarction.
  • the above ingredients are mixed and filled in an airtight cloth to prepare a powder.
  • tablets are prepared by tableting according to a conventional method for preparing tablets.
  • the above ingredients are mixed and filled into gelatin capsules to prepare capsules.
  • each component is added to the purified water to dissolve, the lemon flavor is added, the above ingredients are mixed, the purified water is added, the whole is adjusted to 100 with purified water, and then filled into a brown bottle and sterilized. To prepare a liquid solution.
  • the present invention relates to a pharmaceutical composition for preventing or treating ischemic brain disease, including fimasartan or a salt thereof.
  • Fimasartan of the present invention has an excellent effect in preventing or treating ischemic brain disease by inhibiting cerebral infarction and inhibiting ischemic cell death through anti-inflammatory action at the site of brain injury, and thus usefully used as a preventive or therapeutic agent for ischemic brain disease. Can be.

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating ischemic brain disorders, containing fimasartan or a salt thereof. Fimasartan of the present invention inhibits cerebral infarction and ischemic cell death through an anti-inflammatory action at a brain-injury site, and thus has remarkable effects of preventing or treating ischemic brain disorders.

Description

피마살탄을 포함하는 허혈성 뇌질환 예방 또는 치료용 약학적 조성물Pharmaceutical composition for preventing or treating ischemic brain disease, including fimasartan
본 발명은 피마살탄 또는 그의 염을 포함하는 허혈성 뇌질환 예방 또는 치료용 약학적 조성물에 관한 것이다.  The present invention relates to a pharmaceutical composition for preventing or treating ischemic brain disease, including fimasartan or a salt thereof.
최근에 신경계가 비면역성 기관(immune privileged organ)이라는 기존의 학설과는 달리 다발성경화증(multiple sclerosis), 알쯔하이머 질환(Alzheimer's disease), 뇌졸중 및 각종 뇌손상 등의 신경 질환 시에 중추신경계 내에서도 염증반응이 나타나며 이는 신경퇴행을 야기하는 주요 원인 중의 하나임이 보고되고 있다. 이러한 보고들은 신경계에서 염증반응을 억제하여 신경 보호효과를 얻을 수 있는 가능성을 시사한다.In contrast to the existing theories that the nervous system is an immune privileged organ, the inflammatory response in the central nervous system occurs during neurological diseases such as multiple sclerosis, Alzheimer's disease, stroke and various brain injuries. It is reported that this is one of the major causes of neurodegeneration. These reports suggest the potential for neuroprotective effects by inhibiting inflammatory responses in the nervous system.
상기와 같은 뇌신경 질환 중 뇌졸중은 뇌조직으로 가는 혈액 공급의 감소 또는 차단으로 뇌조직의 허혈상태로 발생하는 뇌허혈(ischemic stroke)과 혈관이 터져 뇌조직에서 출혈을 일으키는 뇌출혈(hemorrhagic stroke)의 두 가지로 크게 구분되며, 특히 뇌허혈은 전체 뇌졸중 환자의 약 80% 정도를 차지할 정도로 심각한 질환이다.Among these neurological diseases, stroke is divided into two types: ischemic stroke, which is caused by an ischemic state of the brain tissue due to a decrease or blocking of blood supply to the brain tissue, and hemorrhagic stroke, which causes blood vessels to bleed and cause bleeding from the brain tissue. In particular, cerebral ischemia is a serious disease that accounts for about 80% of all stroke patients.
뇌졸중 환자에서 혈행 장애로 인해 산소의 공급이 차단 또는 감소되어 야기된 뇌허혈의 중앙 부위(core region)의 세포들은 수초 내지 수분 내에 기능장애가 시작되어 결국은 비가역성 손상을 입게 되는 반면에, 뇌허혈의 주변(penumbra region)의 세포들은 대사 기능에 장애를 받기는 하지만 빠른 시기에 적절한 치료를 받는 경우 비가역적 세포손상을 차단할 수 있다. In stroke patients, the cells in the core region of the cerebral ischemia caused by blockage or reduction of oxygen supply due to a blood circulation disorder begin to malfunction within a few seconds to several minutes and eventually become irreversible damage. Although cells in the penumbra region are impaired in metabolic function, they can block irreversible cell damage if treated properly and quickly.
현재 임상에서 사용되고 있는 뇌졸중 치료제로는 조직 플라스미노겐 액티베이터(TPA) 또는 유로키나제(urokinase)와 같은 혈전 용해제와 혈소판 억제제, 항응고제, 뇌혈관 확장제, Ca2+ 채널(channel) 차단제 및 뇌부종 억제제 등 다양한 기전의 약제들이 있다(Sandercock P. et al., Br. J. Hosp. Med. 47: 731-736, 1992). 그러나 상기 약제들은 치료시기가 지연된 경우 그 효과가 미약하고, 급성 뇌허혈로 인한 뇌허혈의 진행을 효과적으로 차단하지 못하며 비특이적 출혈, 피브리노겐 용해 및 급성재폐색 등의 부작용을 나타내는 것으로 알려져 있다(Scheinberg P. et al., Stroke 25: 1290-1295, 1994).Stroke agents currently in use in clinical trials include thrombolytic agents such as tissue plasminogen activators (TPA) or urokinase, and drugs of various mechanisms, including platelet inhibitors, anticoagulants, cerebrovascular agents, Ca2 + channel blockers, and brain edema inhibitors. (Sandercock P. et al., Br. J. Hosp. Med. 47: 731-736, 1992). However, these drugs have a weak effect when the treatment period is delayed, they do not effectively block the progression of cerebral ischemia due to acute cerebral ischemia, and are known to have side effects such as nonspecific bleeding, fibrinogen lysis, and acute reoccurrence (Scheinberg P. et al. , Stroke 25: 1290-1295, 1994).
즉, 허혈성 뇌질환 치료법으로 사용되고 있는 방법 중 현재까지 임상 실험에서 성공한 혈전 용해술을 제외하면 수많은 신경보호 물질에 대한 시도들은 동물실험에서 거둔만큼의 성과를 임상에서 확인하기 어려운 것으로 보이며, 이에 따라 새로운 허혈성 뇌질환 치료제에 대한 필요성이 있다. In other words, except for thrombolysis that has been successful in clinical trials among the methods used to treat ischemic brain disease, attempts at numerous neuroprotective agents are difficult to confirm in clinical trials as much as the results of animal experiments. There is a need for a treatment for brain disease.
최근에는 안지오텐신이 고혈압 발생원인의 중요한 물질임에 착안하여 안지오텐신 수용체 억제제를 통해 뇌졸중의 강력한 위험인자인 고혈압을 조절하여 뇌졸중을 억제하고자 하는 시도들이 있어왔다. 그러나 아직까지 안지오텐신 수용체 억제제의 혈압 강하 효과에 의존하지 않는 뇌질환 치료제에 관한 보고는 없다. Recently, angiotensin is an important substance causing high blood pressure, and there have been attempts to suppress stroke by controlling hypertension, a powerful risk factor of stroke, through angiotensin receptor inhibitors. However, there are no reports on the treatment of brain diseases that do not depend on the blood pressure-lowering effects of angiotensin receptor inhibitors.
따라서 안전하고 효과적인 허혈성 뇌질환을 치료할 수 있는 새로운 약물의 필요성이 있다. Therefore, there is a need for new drugs that can treat safe and effective ischemic brain diseases.
피마살탄(Fimasartan)은 2-n-부틸-5-디메틸아미노티오카르본일메틸-6-메틸-3-[[2'-(1H-테트라졸-5-일)비페닐-4-일]메틸]피리미딘-4(3H)-온{2-n-Butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidin-4(3H)-one}으로, 하기 구조식을 가지며, ARB(Angiotensin II Receptor Blocker)계열의 혈압 강하제로 알려져있는 물질이다. Fimasartan is 2-n-butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl ] Pyrimidin-4 (3H) -one {2-n-Butyl-5-dimethylaminothiocarbonylmethyl-6-methyl-3-[[2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl] pyrimidin -4 (3H) -one}, which has the following structural formula and is known as an antihypertensive agent of the Angiotensin II Receptor Blocker (ARB) family.
[피마살탄][Pimasaltan]
Figure PCTKR2014009296-appb-I000001
Figure PCTKR2014009296-appb-I000001
피마살탄은 현재 카나브(KANARB) 등의 제품명으로 의약품 허가가 승인되었으며, 경중증도의 본태성 고혈압 환자에서 매우 우월한 혈압강하 효과가 나타나는 것이 알려져 있다. 그러나 피마살탄의 혈압 강하 효과 외에 이의 새로운 용도에 대하여 알려진 바 없다. Fimasartan is currently approved for drug use under the product name of KANARB, etc., and is known to have a very superior blood pressure lowering effect in patients with mild to severe hypertension. However, there is no known new use of pimasartan other than the hypotensive effect.
이에 본 발명자들은 기존 허혈성 뇌질환 치료제의 문제점을 인식하고 기존 약물의 새로운 허혈성 뇌질환 치료 용도를 개발하기 위하여 연구한 결과 본 발명을 완성하였다. Accordingly, the present inventors have completed the present invention as a result of recognizing the problem of the existing ischemic brain disease treatment agent and researching to develop a new ischemic brain disease treatment use of the existing drug.
본 발명자들은 허혈성 뇌질환을 치료하기 위한 다양한 약물을 연구하던 중, 안지오텐신 수용체 억제제인 피마살탄이 기존에 알려지지 않은 허혈성 뇌질환 예방 또는 치료 효과를 나타내는 것을 확인하고 본 발명을 완성하였다. The inventors of the present invention, while studying various drugs for treating ischemic brain disease, confirmed that angiotensin receptor inhibitor pimasartan exhibited a previously known ischemic brain disease prevention or treatment effect and completed the present invention.
따라서 본 발명의 목적은 혈압에 영향을 주지 않으면서 손상된 뇌 부위에서의 항염증 작용을 통해 허혈성 뇌질환을 예방 또는 치료할 수 있는 새로운 약학적 조성물을 제공하는 것이다. Accordingly, an object of the present invention is to provide a new pharmaceutical composition capable of preventing or treating ischemic brain disease through anti-inflammatory action in the damaged brain area without affecting blood pressure.
상기 목적을 달성하기 위하여 본 발명은 피마살탄(Fimasartan) 또는 그의 염을 포함하는 허혈성 뇌질환 예방 또는 치료용 약학적 조성물을 제공한다. In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating ischemic brain disease, including Fimasartan or a salt thereof.
또한 본 발명은, 상기 피마살탄 염은 피마살탄 칼륨염, 염산염, 칼슘염, 황산염, 아디페이트염, 캠실레이트염 및 베실레이트염으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물을 제공한다. In another aspect, the present invention, the fimasartan salt is selected from the group consisting of fimasartan potassium salt, hydrochloride, calcium salt, sulfate, adipate salt, camsylate salt and besylate salt, ischemic brain disease prevention or treatment It provides a pharmaceutical composition.
또한 본 발명은, 상기 허혈성 뇌질환은 중풍, 뇌졸중, 뇌일혈, 뇌경색, 두부손상, 알츠하이머, 혈관성 치매, 크로이츠펠트-야콥병, 혼수 및 쇼크 뇌손상으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물을 제공한다. In another aspect, the present invention is characterized in that the ischemic brain disease is selected from the group consisting of stroke, stroke, cerebral hemorrhage, cerebral infarction, head injury, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, lethargy and shock brain injury. Provided is a prophylactic or therapeutic pharmaceutical composition.
또한 본 발명은, 상기 허혈성 뇌질환은 뇌졸중 또는 뇌경색인, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물을 제공한다.The present invention also provides a pharmaceutical composition for preventing or treating ischemic brain disease, wherein the ischemic brain disease is stroke or cerebral infarction.
또한 본 발명은, 상기 피마살탄은 항염증 작용을 하는 것인, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물을 제공한다. The present invention also provides a pharmaceutical composition for preventing or treating ischemic brain disease, wherein the fimasartan has an anti-inflammatory action.
또한 본 발명은, 상기 조성물은 경구용 제제 또는 주사용 제제인 허혈성 뇌질환 예방 또는 치료용 약학적 조성물을 제공한다. In another aspect, the present invention provides a pharmaceutical composition for preventing or treating ischemic brain disease, which is an oral or injectable preparation.
또한 본 발명은, 상기 피마살탄을 1 내지 240mg 포함하는, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물을 제공한다. The present invention also provides a pharmaceutical composition for preventing or treating ischemic brain disease, comprising 1 to 240 mg of fimasartan.
본 발명의 피마살탄은 뇌 손상 부위에서의 항염증 작용을 통해 뇌경색을 억제하고 허혈성 세포 사멸을 억제하여 허혈성 뇌질환을 예방 또는 치료하는데 우수한 효과가 있다. Fimasartan of the present invention has an excellent effect in preventing or treating ischemic brain disease by inhibiting cerebral infarction and inhibiting ischemic cell death through anti-inflammatory action at the site of brain injury.
도 1은 피마살탄 투여에 따른 허혈성 뇌질환 억제 효과를 확인하기 위한 실험의 모식도를 나타낸 도이다. 1 is a diagram showing a schematic diagram of an experiment for confirming the effect of inhibiting ischemic brain disease according to the administration of fimasartan.
도 2는 뇌경색 랫트 모델의 제조과정을 나타낸 도이다. Figure 2 is a diagram showing the manufacturing process of the cerebral infarction rat model.
도 3은 뇌경색 유발 7일 후, 니슬 염색법을 통해 뇌경색 발생 부피를 확인한 결과를 나타낸 도이다. Figure 3 is a diagram showing the result of confirming the volume of cerebral infarction through the needle stain method 7 days after induction of cerebral infarction.
도 4는 대조군 및 저용량 피마살탄 0.5mg/kg 투여군의 뇌경색 발생 부위 크기를 비교한 결과를 나타낸 도이다.Figure 4 is a diagram showing the results of comparing the size of the cerebral infarction site of the control group and low dose pimasartan 0.5mg / kg administration group.
도 5는 TUNEL 분석법을 통해 사멸된 허혈성 세포 밀도를 분석한 결과를 나타낸 도이다. Figure 5 is a diagram showing the results of analyzing the ischemic cell density killed by the TUNEL assay.
도 6은 피마살탄 1mg/kg, 3mg/kg 투여군에서의 혈압 변화를 확인한 결과를 나타낸 도이다. 6 is a diagram showing the results of confirming the blood pressure change in the 1 mg / kg, 3 mg / kg administration group Fimasartan.
도 7은 저용량 피마살탄 0.5mg/kg 투여군에서의 혈압 변화를 확인한 결과를 나타낸 도이다. Figure 7 shows the results of confirming the blood pressure change in the low-dose pimasartan 0.5mg / kg administration group.
도 8은 Ox6 염색법을 이용한 뇌경색 부위의 염증 세포의 존재를 확인한 결과를 나타낸 도이다. 8 is a diagram showing the results of confirming the presence of inflammatory cells in the cerebral infarction area using the Ox6 staining method.
도 9는 0.5mg/kg의 피마살탄을 투여한 군에서 pSTAT3의 발현양의 변화를 웨스턴 블랏으로 확인한 결과를 나타낸 도이다. 9 is a diagram showing the results of Western blot changes in the expression level of pSTAT3 in the group administered 0.5 mg / kg fimasartan.
도 10은 0.5mg/kg의 피마살탄을 투여한 군에서 iKB 분해 및 COX2 단백질의 발현량의 변화를 웨스턴 블랏으로 확인한 결과를 나타낸 도이다. Figure 10 is a diagram showing the results confirmed by Western blot changes in the expression of iKB degradation and COX2 protein in the group administered 0.5mg / kg fimasartan.
도 11은 피마살탄의 항염증 효과 기전을 나타낸 모식도이다. 11 is a schematic diagram showing the mechanism of anti-inflammatory effect of fimasartan.
도 12는 피마살탄을 투여한 실험군에서의 기능학적 행동성 변화를 운동행동평가를 통해 분석한 결과를 나타낸 도이다. 12 is a diagram showing the results of analyzing the behavioral changes in the behavioral behavior in the experimental group administered with pimasartan.
도 13은 피마살탄 투여군 및 대조군의 생존율을 뇌경색 유발 28일 동안 측정한 결과를 나타낸 도이다. FIG. 13 is a diagram showing the results of measuring the survival rate of the pimasartan-administered group and the control group during the 28 days of infarction.
본 발명은 피마살탄(Fimasartan) 또는 그의 염을 포함하는 허혈성 뇌질환 예방 또는 치료용 약학적 조성물을 제공한다. The present invention provides a pharmaceutical composition for preventing or treating ischemic brain disease comprising Fimasartan or a salt thereof.
본 발명의 피마살탄은 뇌 손상 부위에서의 항염증 작용을 통해 뇌경색을 억제하고 허혈성 세포 사멸을 억제하여 허혈성 뇌질환을 예방 또는 치료하는데 우수한 효과가 있다. 따라서 뇌경색의 위험성이 높은 환자의 항고혈압제 선택에 있어서, 피마살탄을 선택하는 경우 혈압문제를 해결함과 동시에, 뇌경색 또한 효과적으로 예방 또는 치료할 수 있는 장점이 있다. Fimasartan of the present invention has an excellent effect in preventing or treating ischemic brain disease by inhibiting cerebral infarction and inhibiting ischemic cell death through anti-inflammatory action at the site of brain injury. Therefore, in the selection of antihypertensive agents in patients at high risk of cerebral infarction, when selecting Pimasaltan, the blood pressure problem may be solved, and cerebral infarction may be effectively prevented or treated.
본 발명에서 상기 피마살탄 및 그의 약제학적으로 허용되는 염, 이들의 용매화물 또는 이들의 수화물은 결정형이거나 무정형일 수 있으며, 본 발명은 이들의 결정형 및/또는 무정형을 포함한다. The fimasartan and pharmaceutically acceptable salts thereof, solvates thereof or hydrates thereof in the present invention may be crystalline or amorphous, and the present invention includes their crystalline and / or amorphous forms.
본 발명에서, 약제학적으로 허용되는 염은 통상적으로 의약 제조업자가 의약품을 제조하는데 사용하는 무기산염, 유기산염, 금속염을 의미하며, "무기산"으로는 염산, 브롬산, 황산, 인산 등을 사용할 수 있고, "유기산"으로는 구연산, 초산, 젖산, 주석산, 푸마르산, 포름산, 프로피온산, 옥살산, 트리플루오로아세트산, 메탄술폰산, 벤젠술폰산, 말레인산, 벤조산, 글루콘산, 글리콜산, 숙신산, 4-모폴린에탄술폰산, 캠포술폰산, 4-니트로벤젠술폰산, 히드록시-O-술폰산, 4-톨루엔술폰산, 칼룩투론산, 엠보산, 글루탐산, 아스파르트산,아디페이트염, 캠실레이트염 또는 베실레이트염 등을 사용할 수 있으며, "금속"에는 나트륨, 칼륨, 칼슘, 마그네슘 등이 있다.In the present invention, pharmaceutically acceptable salts generally mean inorganic acid salts, organic acid salts, and metal salts used by pharmaceutical manufacturers to prepare medicines. As the "organic acid," hydrochloric acid, bromic acid, sulfuric acid, phosphoric acid, and the like may be used. "Organic acid" includes citric acid, acetic acid, lactic acid, tartaric acid, fumaric acid, formic acid, propionic acid, oxalic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, maleic acid, benzoic acid, gluconic acid, glycolic acid, succinic acid, 4-morpholine Ethanesulfonic acid, camphorsulfonic acid, 4-nitrobenzenesulfonic acid, hydroxy-O-sulfonic acid, 4-toluenesulfonic acid, kalucturonic acid, emboic acid, glutamic acid, aspartic acid, adipate salt, camsylate salt or besylate salt And "metal" includes sodium, potassium, calcium, magnesium, and the like.
본 발명에서, 상기 피마살탄 염은 피마살탄 칼륨염, 염산염, 칼슘염, 황산염, 아디페이트염, 캠실레이트염 또는 베실레이트염인 것이 바람직하다. 이들은 시중에서 구입할 수 있으며, 공지된 방법으로 제조할 수 있다 (예를 들어, 대한민국 특허등록번호 제0354654호 및 제0521980호 등).In the present invention, the fimasartan salt is preferably pimasartan potassium salt, hydrochloride, calcium salt, sulfate, adipate salt, camsylate salt or besylate salt. These are commercially available and can be manufactured by known methods (for example, Korean Patent Registration Nos. 0354654 and 0521980, etc.).
본 발명에서, "용매화물" 중 용매는 유기화합물 제조에 사용되는 통상의 유기용매를 의미하며, 예를 들어, 메탄올, 에탄올, 1-프로판올, 2-프로판올, 1-부탄올, 2-부탄올, 1-아세테이트, 아세톤, 초산, 아니솔, 테트라히드로푸란, 메틸아세테이트, 에틸아세테이트, 프로필아세테이트, 이소프로필아세테이트, 이소부틸아세테이트, n-부틸아세테이트, 디메틸설폭시드, 펜탄, 헵탄 등이 있으나, 이들의 예로 본 발명의 용매화물이 제한되는 것은 아니다.In the present invention, the solvent in the "solvate" means a conventional organic solvent used to prepare an organic compound, for example, methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, 1 Acetates, acetone, acetic acid, anisole, tetrahydrofuran, methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate, n-butyl acetate, dimethyl sulfoxide, pentane, heptane, and the like. The solvates of the present invention are not limited.
본 발명에서, "수화물" 및 "용매화물"은 피마살탄 1몰에 대하여 0.25 내지 10몰비로 함유될 수 있으며, 예를 들어 0.5몰, 1몰, 1.5몰, 2몰, 2.5몰, 3몰, 5몰 등일 수 있으나, 이들의 예로 본 발명이 제한되는 것은 아니다.In the present invention, "hydrate" and "solvate" may be contained in a 0.25 to 10 molar ratio with respect to 1 mole of fimasaltan, for example 0.5 mole, 1 mole, 1.5 mole, 2 mole, 2.5 mole, 3 mole, 5 moles, etc., but the present invention is not limited thereto.
본 발명의 피마살탄 또는 그의 염은 허혈성 뇌질환을 예방 또는 치료하는 효과가 우수하며, 상기 허혈성 뇌질환은 중풍, 뇌졸중, 뇌일혈, 뇌경색, 두부손상, 알츠하이머, 혈관성 치매, 크로이츠펠트-야콥병, 혼수 및 쇼크 뇌손상으로 이루어진 군으로부터 선택되는 것이 바람직하고, 더욱 바람직하게는 뇌졸중 또는 뇌경색일 수 있다. Fimasartan or a salt thereof of the present invention is excellent in preventing or treating ischemic brain disease, and the ischemic brain disease is stroke, stroke, cerebral hemorrhage, cerebral infarction, head injury, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, lethargy and It is preferably selected from the group consisting of shock brain injury, more preferably stroke or cerebral infarction.
본 발명의 피마살탄 또는 그의 염은 안지오텐신 수용체 억제제로 알려진 물질이며, 혈압 조절과 무관한 항염증 작용을 통해 허혈성 뇌질환을 예방 또는 치료하는 효과를 나타낸다. Fimasartan or a salt thereof of the present invention is a substance known as an angiotensin receptor inhibitor, and has an effect of preventing or treating ischemic brain disease through anti-inflammatory action irrelevant to blood pressure control.
보다 구체적으로 상기 피마살탄 또는 그의 염은 뇌경색이 일어난 부위에서 항염증 작용을 나타내어 염증성 인자의 발현을 억제하고 염증 세포의 유입을 억제함으로서 뇌 손상 부위에서의 허혈성 세포 사멸을 막고 뇌 손상 부위를 감소시키는 효과를 나타낸다. More specifically, the fimasartan or salt thereof exhibits anti-inflammatory action at the site of cerebral infarction, thereby inhibiting the expression of inflammatory factors and inhibiting the influx of inflammatory cells, thereby preventing ischemic cell death and reducing the site of brain injury. Effect.
본 발명의 약학적 조성물은 실제 임상 투여 시에 경구 및 비경구의 여러 가지 제형으로 투여될 수 있다. 제제화할 경우에는 보통 사용하는 충진제, 증량제, 결합제, 습윤제, 붕해제 및 계면활성제 등의 희석제 또는 부형제를 사용하여 조제될 수 있다. The pharmaceutical compositions of the present invention may be administered in various formulations, oral and parenteral, in actual clinical administration. When formulated, it may be prepared using diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants commonly used.
특히 본 발명의 약학적 조성물을 경구용 제제 또는 주사용 제제인 것이 바람직하다. In particular, the pharmaceutical composition of the present invention is preferably an oral or injectable preparation.
경구 투여를 위한 고형 제제에는 정제, 환제, 산제, 과립제 및 캡슐제 등이 포함되며, 이러한 고형 제제는 본 발명의 약학적 조성물에 적어도 하나 이상의 부형제, 예를 들면, 전분, 탄산칼슘, 수크로스, 락토오스 및 젤라틴 등을 섞어 조제된다. 또한, 단순한 부형제 이외에 마그네슘, 스티레이드, 탈크 같은 윤활제도 사용될 수 있다. Solid preparations for oral administration include tablets, pills, powders, granules, and capsules, and the like, which may be used in the pharmaceutical compositions of the present invention at least one excipient such as starch, calcium carbonate, sucrose, It is prepared by mixing lactose and gelatin. In addition to the simple excipients, lubricants such as magnesium, styrene, and talc may also be used.
경구 투여를 위한 액상 제제로는 현탁제, 내용액제, 유제 및 시럽제 등이 해당되는데 흔히 사용되는 단순 희석제인 물, 리퀴드 파라핀 이외에 여러 가지 부형제, 예를 들면 습윤제, 감미제, 방향제 및 보존제 등이 포함될 수 있다. Liquid preparations for oral administration include suspensions, solutions, emulsions and syrups, and may include various excipients such as wetting agents, sweeteners, fragrances and preservatives, in addition to commonly used simple diluents such as water and liquid paraffin. have.
비경구 투여를 위한 제제에는 멸균된 수용액, 비수성용제, 현탁제, 유제, 동결건조제제 및 좌제가 포함된다. 비수성용제와 현탁용제로는 프로필레글리콜, 폴리에틸렌글리콜, 올리브 오일과 같은 식물성 기름, 에틸올레이트와 같은 주사 가능한 에스테르 등이 사용될 수 있다. 좌제의 기제로는 위텝솔(witepsol), 마크로골, 트윈 61, 카카오지, 라우린지, 글리세롤 및 젤라틴 등이 사용될 수 있다. 본 발명의 약학적 조성물은 비경구 투여시 피하주사, 정맥주사 또는 근육내 주사를 통하여 투여될 수 있다. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations and suppositories. As the non-aqueous solvent and the suspension solvent, propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like can be used. As the base of the suppository, witepsol, macrogol, tween 61, cacao butter, laurin butter, glycerol, gelatin and the like can be used. The pharmaceutical composition of the present invention may be administered by subcutaneous injection, intravenous injection or intramuscular injection during parenteral administration.
본 발명의 약학 조성물은 약학적으로 허용되는 담체를 첨가하여 제제화할 수 있으며, 제제화에 관한 내용은 Remington's Pharmaceutical Science(최근판), Mack Publishing Company, Easton PA의 문헌을 참조할 수 있다. 상기 약학적으로 허용 가능한 담체는 의약 발명 부분에 속하는 통상의 기술자에게 의약 조성물 제조시 통상적으로 사용되는 것을 의미한다. 예를 들어, 락토오즈, 덱스트로오즈, 수크로오스, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로오즈, 메틸 셀룰로오즈, 미정질 셀룰로오스, 폴리비닐 피롤리돈, 물, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유 등이 있다. 또한, 약학적으로 허용되는 담체는 충진제, 증량제, 결합제, 습윤제, 붕해제, 계면활성제 등의 희석제 또는 부형제를 포함한다. The pharmaceutical composition of the present invention may be formulated by adding a pharmaceutically acceptable carrier, and the formulation may be referred to Remington's Pharmaceutical Science (Recent Edition), Mack Publishing Company, Easton PA. The pharmaceutically acceptable carrier refers to those commonly used in preparing pharmaceutical compositions to those skilled in the art. For example, lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pi Ralidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. Pharmaceutically acceptable carriers also include diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrants, surfactants and the like.
그러나, 상기 열거된 약제학적으로 허용되는 담체 등으로 본 발명이 한정되는 것은 아니며, 이들은 단지 예시에 불과하다.However, the present invention is not limited to the above-listed pharmaceutically acceptable carriers and the like, which are merely exemplary.
상기 약학적 조성물에 함유되는 피마살탄의 적용량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여경로 및 기간에 따라 다르지만, 경우에 따라 적절하게 선택될 수 있다. 예를 들면, 60kg 정도의 일반 성인을 기준으로 피마살탄을 1일 약1 내지 240mg, 바람직하게는 30 내지 180mg의 용량으로 경구 투여할 수 있으며, 상기 적용은 하루에 한번 또는 수회 나누어 적용할 수도 있다. The amount of fimasartan contained in the pharmaceutical composition depends on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected in some cases. For example, fimasartan may be orally administered at a dose of about 1 to 240 mg, preferably 30 to 180 mg per day, based on a normal adult weighing about 60 kg, and the application may be applied once or several times a day. .
따라서, 상기 약학 조성물은 피마살탄 또는 이의 염을 약 1mg 내지 240mg으로 포함할 수 있으며, 바람직하게는 약 30 내지 180mg 포함할 수 있다. Accordingly, the pharmaceutical composition may include about 1 mg to 240 mg of fimasartan or a salt thereof, and preferably about 30 to 180 mg.
상기 약학 조성물은 인간 등의 포유동물에 다양한 경로로, 예를 들면, 경구, 정맥, 근육, 또는 피하 주사에 의해 적용될 수 있다. The pharmaceutical composition can be applied to mammals such as humans by various routes, for example by oral, intravenous, intramuscular, or subcutaneous injection.
또한 본 발명의 의약조성물은 피마살탄 외에 허혈성 뇌질환의 예방 또는 치료 효과를 나타내는 유효성분을 1종 이상 함유할 수 있다.In addition, the pharmaceutical composition of the present invention may contain at least one active ingredient exhibiting a prophylactic or therapeutic effect in addition to fimasartan.
또한 본 발명의 의약조성물은 허혈성 뇌질환의 개선, 완화, 치료 또는 예방을 위하여 단독으로, 또는 수술, 호르몬 치료, 약물 치료 및 생물학적 반응 조절제를 사용하는 방법들과 병용하여 사용할 수 있다.In addition, the pharmaceutical composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, drug treatment and biological response modifiers for the improvement, alleviation, treatment or prevention of ischemic brain disease.
본 발명의 피마살탄은 또는 그의 염은 항염증 작용을 통해 혈압 강하 기전과 무관하게 허혈성 뇌질환으로부터 뇌를 보호하는 역할을 수행할 수 있으며, 통상 사용되는 것과 비교하여 저용량으로 장기간 투여하는 경우에도 독성없이 항염증 작용 및 뇌경색 완화 효과가 매우 우수하므로, 본 발명은 허혈성 뇌질환 예방 또는 치료를 위하여 피마살탄을 포함하는 새로운 조성물의 용도를 제공한다. Fimasartan or the salt thereof of the present invention may play a role of protecting the brain from ischemic brain disease regardless of the mechanism of lowering blood pressure through anti-inflammatory action, and is toxic even when administered at a low dose for a long time as compared to conventional use. Without anti-inflammatory action and cerebral infarction effect is very good, the present invention provides the use of a new composition comprising fimasartan for the prevention or treatment of ischemic brain disease.
또한 본 발명은 허혈성 뇌질환 예방 또는 치료를 위한 피마살탄(Fimasartan) 또는 그의 염의 용도를 제공한다. The present invention also provides the use of Fimasartan or a salt thereof for preventing or treating ischemic brain disease.
또한 본 발명은 피마살탄(Fimasartan) 또는 그의 염을 포함하는 조성물을 투여하여 허혈성 뇌질환을 예방 또는 치료하는 방법을 제공한다. The present invention also provides a method for preventing or treating ischemic brain disease by administering a composition comprising Fimasartan or a salt thereof.
상기 조성물은 대상체에 투여될 수 있으며, 대상체에 투여하는 경우 허혈성 뇌질환을 예방 또는 치료하는데 유효한 양으로 투여될 수 있다. The composition may be administered to a subject, and when administered to the subject, may be administered in an amount effective to prevent or treat ischemic brain disease.
상기 대상체는 동물을 말하며, 전형적으로 본 발명의 피마살탄 또는 그의 염을 이용한 치료로 유익한 효과를 나타낼 수 있는 포유동물이다. 이러한 대상체의 바람직한 예에는 인간과 같은 영장류가 포함된다. 또한 이와 같은 대상체들은 허혈성 뇌질환을 갖거나 이와 같은 증상을 가질 위험이 있는 대상체들이 모두 포함된다. The subject refers to an animal, and is typically a mammal that may have a beneficial effect with treatment with fimasartan or a salt thereof of the present invention. Preferred examples of such subjects include primates, such as humans. Such subjects also include all subjects with or at risk of having ischemic brain disease.
상기 유효한 양은 단일 또는 다중 용량으로, 단독 또는 하나 또는 그 이상의 다른 치료제 등과의 조합으로, 대상체에서 원하는 성과 또는 객관적이거나 또는 주관적인 잇점을 제공하는 양을 의미한다. Such effective amount means an amount that provides a desired outcome or objective or subjective benefit in a subject, in single or multiple doses, alone or in combination with one or more other therapeutic agents, and the like.
또한 본 발명은 허혈성 뇌질환 예방 또는 치료용 약제의 제조를 위한 피마살탄(Fimasartan) 또는 그의 염의 사용을 제공한다. The present invention also provides the use of Fimasartan or a salt thereof for the manufacture of a medicament for preventing or treating ischemic brain disease.
본 발명에 있어서, 허혈성 뇌질환은 중풍, 뇌졸중, 뇌일혈, 뇌경색, 두부손상, 알츠하이머, 혈관성 치매, 크로이츠펠트-야콥병, 혼수 및 쇼크 뇌손상으로 이루어진 군으로부터 선택되는 것이 바람직하고, 더욱 바람직하게는 뇌졸중 또는 뇌경색일 수 있다. In the present invention, the ischemic brain disease is preferably selected from the group consisting of stroke, stroke, cerebral hemorrhage, cerebral infarction, head injury, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, lethargy and shock brain injury, more preferably stroke Or cerebral infarction.
또한 본 발명의 피마살탄 또는 그의 염은 피마살탄 칼륨염, 염산염, 칼슘염, 황산염, 아디페이트염, 캠실레이트염 및 베실레이트염으로 이루어진 군으로부터 선택되는 것일 수 있다.In addition, the fimasartan or salt thereof of the present invention may be selected from the group consisting of fimasartan potassium salt, hydrochloride, calcium salt, sulfate, adipate salt, camsylate salt and besylate salt.
본 발명의 피마살탄 또는 그의 염은 안지오텐신 수용체 억제제로 알려진 물질이며, 혈압 조절과 무관한 항염증 작용을 통해 허혈성 뇌질환을 예방 또는 치료하는 효과를 나타낸다. Fimasartan or a salt thereof of the present invention is a substance known as an angiotensin receptor inhibitor, and has an effect of preventing or treating ischemic brain disease through anti-inflammatory action irrelevant to blood pressure control.
또한 본 발명에 있어서, 상기 피마살탄 또는 그의 염은 약 1mg 내지 240mg일 수 있으며, 바람직하게는 약 30 내지 180mg 일 수 있다.In addition, in the present invention, the fimasartan or a salt thereof may be about 1mg to 240mg, preferably about 30 to 180mg.
이상 본 명세서에 기재된 수치값은 달리 명시되어 있지 않은 한 균등범위까지 포함하는 것으로 해석되어야 한다. The numerical values set forth herein are to be construed to include equivalent ranges unless otherwise specified.
이하, 본 발명의 이해를 돕기 위하여 바람직한 실시예, 제제예를 제시한다. 그러나 하기의 실시예, 제제예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예 또는 제제예에 의해 본 발명의 내용이 한정되는 것은 아니다.Hereinafter, preferred examples and formulation examples are provided to aid the understanding of the present invention. However, the following Examples and Formulation Examples are provided only for easier understanding of the present invention, and the contents of the present invention are not limited by Examples or Formulation Examples.
실시예 1. 피마살탄의 뇌경색 치료 효과 Example 1 Effect of Fimasartan on Cerebral Infarction
1.1 뇌경색 모델의 제조 및 피마살탄 투여1.1 Preparation of Cerebral Infarction Model and Administration of Pimasaltan
뇌경색 모델로 사용된 Sprague-Dawley 랫트는 구입하여 사용하였으며, 모든 랫트는 정상 혈압을 가지고 있는 것을 확인하였다. Sprague-Dawley 랫트에 뇌경색을 유발하기 4주 전부터 1일 1회 경구로 피마살탄을 저용량 0.5mg/kg, 일반 투여용량 1mg/kg, 3mg/kg 으로 투여하였으며, 실험군의 최종 부피와 동량의 PBS만을 투여한 군을 대조군으로 삼았다. 이 후 좌-중대뇌동맥(Middle Cerebral Artery; MCA)에서 60분 동안 폐색-재관류 손상을 통한 폐색-재관류 뇌경색 모델을 제조하였다. 좌-중대뇌동맥의 폐색은 수정된 Longa technique(Zea Longa E, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989;20: 84-91.)을 이용하였다. Sprague-Dawley rats were used as cerebral infarction model and all rats were confirmed to have normal blood pressure. Sprague-Dawley rats received oral fimasartan at a low dose of 0.5 mg / kg, normal dose of 1 mg / kg, and 3 mg / kg once a week, four weeks before cerebral infarction, and the final volume and the same amount of PBS in the experimental group. The administered group was used as a control. A model of obstruction-reperfusion cerebral infarction via occlusion-reperfusion injury for 60 minutes was then made in the left-middle Cerebral Artery (MCA). Occlusion of the left-middle cerebral artery was performed using a modified Longa technique (Zea Longa E, Weinstein PR, Carlson S, Cummins R. Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke. 1989; 20: 84-91.).
뇌경색 랫트 모델의 제조를 도 2에 나타내었다. The preparation of the cerebral infarction rat model is shown in FIG. 2.
1.2 피마살탄 투여에 따른 뇌경색 크기 확인1.2 Identification of Cerebral Infarct Size Following Fimasartan Administration
상기 1.1의 방법에 따라 랫트에서 뇌경색을 유발하고 7일 후 랫트에서 뇌를 적출하여 뇌경색의 크기 변화를 측정하였다. According to the method of 1.1, the brain was induced in the rat 7 days after the brain was extracted from the rat and the size change of the cerebral infarction was measured.
염기성 아닐린염료로 신경조직을 염색하는 니슬 염색법을 이용하여 뇌경색이 발생된 부위를 확인하였으며, 이미지 분석을 통해 뇌경색의 크기를 구체적으로 측정하였다.  The area where cerebral infarction occurred was identified by using a Nisle staining method to stain neural tissue with basic aniline dye, and the size of cerebral infarction was specifically measured through image analysis.
결과를 도 3 및 도 4에 나타내었다. The results are shown in FIGS. 3 and 4.
도 3에 나타낸 바와 같이 뇌경색 유발 7일 후 뇌경색 부피를 측정한 결과, 저용량 및 일반 투여용량 피마살탄 투여군 모두에서 대조군에 비해 뇌경색이 발생된 부위가 감소되어 있는 것을 확인하였다. 특히 저용량의 피마살탄 0.5mg/kg을 투여한 실험군의 경우 46.2mm3 으로 대조군인 PBS 투여군에서의 153.4mm3 과 비교하여 현저하게 뇌경색 발생 부피가 감소되어 있음을 확인할 수 있었다. As shown in FIG. 3, the cerebral infarction volume was measured 7 days after the induction of cerebral infarction. As a result, it was confirmed that the site where cerebral infarction occurred was reduced in both the low dose and the general dose fimasartan-administered group. In particular, the test group the administration of castor oil saltan 0.5mg / kg with a low dose of 46.2mm 3 was confirmed that considerably as compared to 153.4mm 3 in the PBS treated control group is reduced cerebral infarction volume occurs.
도 4에 나타낸 바와 같이, 저용량의 피마살탄 0.5mg/kg을 투여한 실험군에서는 대조군과 비교하여 현저하게 뇌경색 크기가 감소되었음이 이미지 분석을 통해 추가적으로 확인되었다. 뇌경색 크기의 중간값은 저용량의 피마살탄 0.5mg/kg을 투여한 실험군에서 36.9mm2, 대조군에서 166.2mm2으로 나타났다. As shown in FIG. 4, it was further confirmed through image analysis that the cerebral infarct size was significantly reduced in the experimental group administered with a low dose of fimasartan 0.5mg / kg compared to the control group. The median size of the cerebral infarction was found in the test group the administration of castor oil saltan 0.5mg / kg low dose of 36.9mm 2, in the control group to 166.2mm 2.
1.3 피마살탄 투여에 따른 허혈성 세포 사멸 감소 1.3 Reduced Ischemic Cell Death Following Administration of Fimasartan
상기 1.1의 방법에 따라 랫트에서 뇌경색을 유발하고 7일 후 TUNEL 분석법을 통해 허혈성 세포 사멸 수를 분석하였다. Ischemic cell death was analyzed by TUNEL assay 7 days after inducing cerebral infarction in the rat according to the method of 1.1.
결과를 도 5에 나타내었다. The results are shown in FIG.
도 5에 나타낸 바와 같이, 사멸된 허혈성 세포를 나타내는 TUNEL 양성 세포의 밀도는 피마살탄 투여군에서 현저하게 감소되었음을 확인하였다. 저용량의 피마살탄 0.5mg/kg을 투여한 실험군에서 TUNEL 양성 세포의 밀도는 1302.5/mm2, 대조군에서 553/mm2으로 나타났다. 즉, 피마살탄의 투여는 허혈에 의해 유발되는 세포의 사멸을 억제함으로서 뇌경색을 억제하는 것으로 확인되었다. As shown in Figure 5, it was confirmed that the density of TUNEL positive cells showing dead ischemic cells was significantly reduced in the Pimasaltan administration group. TUNEL positive cells had a density of 1302.5 / mm 2 and 553 / mm 2 in the control group in the low dose Fimasartan 0.5mg / kg. That is, the administration of fimasartan was found to suppress cerebral infarction by inhibiting the death of cells caused by ischemia.
이와 같은 결과를 통해, 안지오텐신 수용체인 피마살탄은 허혈에 의한 세포 사멸을 방지하고, 뇌경색을 억제할 수 있는 새로운 의약 용도가 있음을 확인하였다. Through these results, it was confirmed that pimasartan, angiotensin receptor, prevents cell death due to ischemia and has new medicinal uses that can suppress cerebral infarction.
실시예 2. 피마살탄의 투여군의 혈압 변화 확인 Example 2 Confirmation of Change in Blood Pressure of Administered Fimasartan
상기 실시예 1에서 확인한 피마살탄의 뇌경색 억제 효과가 피마살탄의 혈압 조절에 의하여 나타나는 것인지 여부를 추가적으로 확인하였다. 이는 뇌경색 유발 위험 요인인 혈압 조절에 의하여 피마살탄의 뇌경색 억제 효과가 나타나는 것인지 여부를 확인하기 위한 것이다. 피마살탄 투여에 따른 뇌경색 유발 랫트의 혈압 변화를 확인하기 위하여 상기 1.1의 랫트에서 뇌경색 유발 전 및 뇌경색 유발 후의 혈압 변화를 측정하여 비교하였다. 혈압은 뇌경색 유발 전 4주부터 뇌경색 유발 후 7일 후까지 측정하였다. It was further confirmed whether the effect of inhibiting cerebral infarction of the fimasartan confirmed in Example 1 was indicated by the blood pressure control of the fimasartan. This is to determine whether the anti-infarction effect of pimasartan is exhibited by blood pressure control, which is a risk factor for inducing cerebral infarction. In order to confirm the change in blood pressure of cerebral infarction-induced rats following pimasartan administration, the blood pressure changes before and after infarction-induced cerebral infarction were measured in the rats of 1.1. Blood pressure was measured from 4 weeks before infarction to 7 days after infarction.
결과를 도 6 및 도 7에 나타내었다. The results are shown in FIGS. 6 and 7.
도 6에 나타낸 바와 같이, 일반 투여 용량인 피마살탄 1mg/kg, 3mg/kg을 투여한 랫트 모델에서는 대조군과 비교하여 수축기, 이완기 모두 유의한 평균 혈압 감소가 나타났다. 반면 도 7에 나타낸 바와 같이 저용량의 피마살탄 0.5mg/kg을 투여한 랫트에서는 뇌경색 유발전 4주 및 뇌경색 유발 후 7일 동안 유의한 혈압 감소가 관찰되지 않았으며, 대조군과 유사한 수준의 혈압 변화 양상을 보였다. As shown in Figure 6, the rat model administered the normal dose of pimasartan 1mg / kg, 3mg / kg showed a significant mean blood pressure decrease in both systolic and diastolic compared to the control group. On the other hand, as shown in FIG. 7, the rats treated with 0.5 mg / kg of low dose of pimasartan showed no significant blood pressure reduction for 4 weeks before and 7 days after induction of cerebral infarction. Showed.
상기와 같은 결과에 따라, 저용량의 피마살탄 0.5mg/kg은 혈압을 변화시키지 않으면서도 뇌경색 억제 효과가 있다는 것을 확인하였으며 피마살탄의 뇌경색 억제 효과는 혈압 조절과 무관하게 발생된다는 것을 알 수 있었다. According to the above results, it was confirmed that low dose of fimasartan 0.5mg / kg has an effect of inhibiting cerebral infarction without changing blood pressure, and it was found that the effect of pimasartan's cerebral infarction was generated irrespective of blood pressure control.
실시예 3. 피마살탄 투여에 따른 염증 반응 확인 Example 3 Confirmation of Inflammatory Response Following Administration of Fimasartan
실시예 1에서 가장 우수한 뇌경색 억제 효과를 나타내는 용량으로 확인된 0.5mg/kg 피마살탄 투여군에서 뇌경색 유발 7일 후 뇌경색 주변부의 염증 세포 밀도를 면역조직화학 분석을 통해 측정하고 단백질의 발현 변화를 웨스턴 블랏을 이용하여 확인하여 뇌경색 억제 기전을 분석하였다. In the 0.5 mg / kg pimasartan-administered group identified as the dose showing the best cerebral infarction effect in Example 1, the density of inflammatory cells at the periphery of cerebral infarction was measured by immunohistochemistry and 7 days after the infarction. The mechanism of inhibition of cerebral infarction was analyzed by confirming using.
3.1 면역조직화학 분석 결과3.1 Immunohistochemical Analysis
뇌경색 주변부의 염증세포 밀도는 Ox6을 이용한 면역조직화학법 염색으로 측정하였다. Ox6은 소식세포(microphage) 및 미세아교세포(microglia)의 특이적 표지자이며 Ox6 양성 세포의 밀도를 측정함으로서 염증 유발 정도를 확인할 수 있다. Inflammatory cell density around the cerebral infarction was measured by immunohistochemical staining with Ox6. Ox6 is a specific marker of microphage and microglia and can determine the degree of inflammation by measuring the density of Ox6 positive cells.
결과를 도 8에 나타내었다. The results are shown in FIG.
도 8에 나타낸 바와 같이, 피마살탄 0.5mg/kg 투여군의 뇌경색 주변 부위에서는 Ox6 양성 세포 밀도가 대조군에 비하여 현저하게 감소된 것을 확인하였다. 보다 구체적으로 저용량의 피마살탄 0.5mg/kg을 투여한 실험군에서 Ox6 양성 세포의 밀도의 중간값은 157/mm2, 대조군에서 654/mm2로 나타났다.As shown in FIG. 8, it was confirmed that Ox6 positive cell density was significantly decreased in the region around the cerebral infarction of the pimasartan 0.5 mg / kg administration group compared with the control group. More specifically, the median density of Ox6 positive cells in the experimental group administered 0.5 mg / kg of low dose fimasartan was 157 / mm 2 and 654 / mm 2 in the control group.
3.2 면역조직화학 분석 결과3.2 Immunohistochemical Assay
염증성 인자의 단백질 발현량의 변화를 확인하기 위하여 웨스턴 블랏을 수행하였다. 뇌경색 유도 후 2일 후 뇌경색 주변부 조직에서의 pSTAT3 및 COX2, iKB 단백질 발현을 통상의 웨스턴 블랏 방법에 의하여 수행하였으며, 액틴(Actin)을 대조군으로 하였다. Western blots were performed to confirm changes in protein expression levels of inflammatory factors. Two days after cerebral infarction induction, pSTAT3, COX2, and iKB protein expression in peripheral tissues of cerebral infarction were performed by a conventional Western blot method, and actin was used as a control.
결과를 도 9에 나타내었다. The results are shown in FIG.
도 9에 나타낸 바와 같이, 0.5mg/kg의 피마살탄을 투여한 군에서 pSTAT3의 발현량을 측정한 결과, 뇌경색이 유도된 좌반구에서의 pSTAT3의 발현량은 대조군과 비교하여 감소된 것으로 확인되었다. As shown in FIG. 9, as a result of measuring the expression level of pSTAT3 in the group administered 0.5 mg / kg of pimasartan, it was confirmed that the expression level of pSTAT3 in the cerebral infarction-induced left hemisphere was reduced compared to the control group.
또한 도 10 에 나타낸 바와 같이, iKB의 분해가 감소하고 COX2 단백질의 발현 역시 억제된 것을 확인하였다. iKB의 분해는 염증 반응을 유발하고, COX2는 허혈 후 전-염증성 단백질로 작용하므로, 피마살탄 투여에 의하여 이들 인자가 각각 분해 감소 및 발현 억제되는 것으로 보아 피마살탄의 투여는 뇌경색 부위의 염증 반응 억제를 통해 뇌경색을 억제하는 것임을 확인하였다. 관련 모식도를 도 11에 나타내었다. In addition, as shown in FIG. 10, it was confirmed that degradation of iKB was reduced and expression of COX2 protein was also suppressed. Since the degradation of iKB causes an inflammatory response and COX2 acts as a pro-inflammatory protein after ischemia, the administration of pimasartan suppresses the inflammatory response of the cerebral infarction because it is shown that these factors are reduced and inhibited expression by pimasartan administration, respectively. It was confirmed that the suppression of cerebral infarction. The related schematic is shown in FIG.
실시예 4. 피마살탄 투여에 따른 기능학적 회복 효과Example 4 Functional Recovery Effect of Fimasartan Administration
피마살탄 투여에 의하여 뇌경색이 완화된 랫트에서 실제로 기능학적 행동성이 개선되는지 여부를 뇌경색 유발 후 14일 동안 확인하였다. 기능학적 행동성 분석을 위한 운동행동평가는 수정된 앞다리 배치 검사(Modified limb placing test, MLPT)를 이용하여 수행(S. W. Jeong, K. Chu, K. H. Jung, S. U. Kim, M. Kim, and J. K. Roh, "Human neural stem cell transplantation promotes functional recovery in rats with experimental intracerebral hemorrhage," Stroke, Vol.34, No.9, pp.2258-2263, 2003)하였으며, 랫트의 행동양상을 비디오 촬영한 후 제3자의 블라인드 테스트를 통해 데이터를 분석하였다. 평가 점수는 신경학적 손상(Neurologic Deficit) 증가 정도에 따라 1 내지 8로 측정하였으며, 정상인 경우를 0으로 하였다. It was confirmed for 14 days after induction of cerebral infarction whether pimasartan administration actually improved functional behavior in rats with relieving cerebral infarction. Motor behavior evaluation for functional behavior analysis was performed using a modified limb placing test (MLPT) (SW Jeong, K. Chu, KH Jung, SU Kim, M. Kim, and JK Roh, "Human neural stem cell transplantation promotes functional recovery in rats with experimental intracerebral hemorrhage," Stroke, Vol. 34, No. 9, pp. 2258-2263, 2003). The data was analyzed by testing. The evaluation score was determined to be 1 to 8 according to the extent of neurologic deficit (Neurologic Deficit), the normal case was 0.
결과를 도 12에 나타내었다. The results are shown in FIG.
도 12에 나타낸 바와 같이, 대조군의 경우 뇌경색 유발 후 신경학적 손상에 의한 행동양상이 6점으로 나타났으나, 피마살탄을 투여한 실험군에서는 행동양상의 변화가 4점으로 낮게 나타났으며, 14일 차에는 2점대의 양상을 보여 대조군과 비교하여 뇌경색으로 인한 기능적 행동 양상의 변화도 더욱 완화되어 있음을 확인하였다. 즉, 피마살탄을 투여하는 경우 뇌경색에 기인한 신경손상이 완화되므로 신경 손상에 따른 신체 마비 증상 등이 완화될 수 있는 것을 알 수 있다. As shown in FIG. 12, the control group exhibited 6 behavioral patterns due to neurological injury after cerebral infarction, but the change in behavioral pattern was lower to 4 points in the experimental group administered with pimasartan, and 14 days The difference between the two points was shown in the tea, and the changes in functional behavior due to cerebral infarction were also alleviated. That is, when administering fimasartan, nerve damage due to cerebral infarction is alleviated, and thus, physical paralysis due to nerve damage may be alleviated.
실시예 5. 피마살탄 투여에 따른 랫트 사망률 Example 5 Rat Mortality Following Fimasartan Administration
4주 동안의 피마살탄 투여가 뇌경색에 의한 랫트 사망률을 낮출 수 있는지 확인하기 위하여 뇌경색 유발 28일 후 랫트의 생존률을 확인하였다. To determine whether 4 weeks of pimasartan administration could reduce rat mortality due to cerebral infarction, the survival rate of rats was examined 28 days after infarction.
결과를 도 13에 나타내었다. The results are shown in FIG.
도 13에 나타낸 바와 같이, 피마살탄을 투여하지 않은 대조군의 경우 뇌경색 유발 28일 후 생존율이 절반 이하로 감소하는 반면, 피마살탄을 투여한 실험군의 경우 28일 이후에도 0.8이상의 높은 생존율을 보였다. 즉, 피마살탄을 투여한 실험군은 뇌경색이 억제됨으로서 뇌 손상에 의한 사망률도 효과적으로 낮출 수 있는 것을 알 수 있다. As shown in FIG. 13, the control group that did not receive fimasartan showed a survival rate of less than half after 28 days of infarction, whereas the experimental group that received fimasartan showed a high survival rate of 0.8 or more after 28 days. In other words, it can be seen that the experimental group administered with pimasartan can effectively lower the death rate due to brain injury by suppressing cerebral infarction.
제제예 1. 산제의 제조Formulation Example 1 Preparation of Powder
피마살탄 20 mgFimasaltan 20 mg
유당 100 mg Lactose 100 mg
탈크 10 mg Talc 10 mg
상기의 성분들을 혼합하고 기밀포에 충진 하여 산제를 제조한다.The above ingredients are mixed and filled in an airtight cloth to prepare a powder.
제제예 2. 정제의 제조Formulation Example 2 Preparation of Tablet
피마살탄 10 mgFimasaltan 10 mg
옥수수전분 100 mg Corn starch 100 mg
유당 100 mg Lactose 100 mg
스테아린산 마그네슘 2 mg2 mg magnesium stearate
상기의 성분들을 혼합한 후 통상의 정제의 제조방법에 따라서 타정하여 정제를 제조한다.After mixing the above components, tablets are prepared by tableting according to a conventional method for preparing tablets.
제제예 3. 캅셀제의 제조 Formulation Example 3 Preparation of Capsule
피마살탄 10 mgFimasaltan 10 mg
결정성 셀룰로오스 3 mg3 mg of crystalline cellulose
락토오스 14.8 mgLactose 14.8 mg
마그네슘 스테아레이트 0.2 mgMagnesium Stearate 0.2 mg
통상의 캡슐제 제조방법에 따라 상기의 성분을 혼합하고 젤라틴 캡슐에 충전하여 캡슐제를 제조한다.According to a conventional capsule preparation method, the above ingredients are mixed and filled into gelatin capsules to prepare capsules.
제제예 4. 주사제의 제조Formulation Example 4 Preparation of Injection
피마살탄 10 mgFimasaltan 10 mg
만니톨 180 mg Mannitol 180 mg
주사용 멸균 증류수 2974 mgSterile distilled water for injection 2974 mg
Na2HPO4,12H2O 26 mgNa 2 HPO 4 , 12H 2 O 26 mg
통상의 주사제의 제조방법에 따라 1 앰플당(2) 상기의 성분 함량으로 제조한다.According to the conventional method for preparing an injection, it is prepared in the amount of the above ingredient (2) per ampoule.
제제예 5. 액제의 제조Formulation Example 5 Preparation of Liquid
피마살탄 10 mgFimasaltan 10 mg
이성화당 10 g10 g of isomerized sugar
만니톨 5 g5 g of mannitol
정제수 적량Purified water
통상의 액제의 제조방법에 따라 정제수에 각각의 성분을 가하여 용해시키고 레몬 향을 적량 가한 다음 상기의 성분을 혼합한 다음 정제수를 가하여 전체를 정제수를 가하여 전체 100로 조절한 후 갈색병에 충진 하여 멸균시켜 액제를 제조한다.According to the conventional method of preparing a liquid solution, each component is added to the purified water to dissolve, the lemon flavor is added, the above ingredients are mixed, the purified water is added, the whole is adjusted to 100 with purified water, and then filled into a brown bottle and sterilized. To prepare a liquid solution.
본 발명은 피마살탄 또는 그의 염을 포함하는 허혈성 뇌질환 예방 또는 치료용 약학적 조성물에 관한 것이다. 본 발명의 피마살탄은 뇌 손상 부위에서의 항염증 작용을 통해 뇌경색을 억제하고 허혈성 세포 사멸을 억제하여 허혈성 뇌질환을 예방 또는 치료하는데 우수한 효과가 있으므로, 허혈성 뇌질환의 예방 또는 치료제로서 유용하게 이용할 수 있다.  The present invention relates to a pharmaceutical composition for preventing or treating ischemic brain disease, including fimasartan or a salt thereof. Fimasartan of the present invention has an excellent effect in preventing or treating ischemic brain disease by inhibiting cerebral infarction and inhibiting ischemic cell death through anti-inflammatory action at the site of brain injury, and thus usefully used as a preventive or therapeutic agent for ischemic brain disease. Can be.

Claims (10)

  1. 피마살탄(Fimasartan) 또는 그의 염을 포함하는 허혈성 뇌질환 예방 또는 치료용 약학적 조성물. Pharmaceutical composition for preventing or treating ischemic brain disease, including Fimasartan or salts thereof.
  2. 제1항에 있어서, 상기 피마살탄 염은 피마살탄 칼륨염, 염산염, 칼슘염, 황산염, 아디페이트염, 캠실레이트염 및 베실레이트염으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물. The method of claim 1, wherein the fimasartan salt is selected from the group consisting of fimasartan potassium salt, hydrochloride, calcium salt, sulfate, adipate salt, camsylate salt and besylate salt. Therapeutic pharmaceutical composition.
  3. 제1항에 있어서, 상기 허혈성 뇌질환은 중풍, 뇌졸중, 뇌일혈, 뇌경색, 두부손상, 알츠하이머, 혈관성 치매, 크로이츠펠트-야콥병, 혼수 및 쇼크 뇌손상으로 이루어진 군으로부터 선택되는 것을 특징으로 하는, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물.The ischemic brain disease of claim 1, wherein the ischemic brain disease is selected from the group consisting of stroke, stroke, cerebral hemorrhage, cerebral infarction, head injury, Alzheimer's disease, vascular dementia, Creutzfeldt-Jakob disease, lethargy and shock brain injury. Pharmaceutical compositions for preventing or treating diseases.
  4. 제3항에 있어서, 상기 허혈성 뇌질환은 뇌졸중 또는 뇌경색인, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물. The pharmaceutical composition for preventing or treating ischemic brain disease according to claim 3, wherein the ischemic brain disease is stroke or cerebral infarction.
  5. 제1항에 있어서, 상기 피마살탄은 항염증 작용을 하는 것인, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물. The pharmaceutical composition for preventing or treating ischemic brain disease of claim 1, wherein the fimasartan has an anti-inflammatory action.
  6. 제1항에 있어서, 상기 조성물은 경구용 제제 또는 주사용 제제인 허혈성 뇌질환 예방 또는 치료용 약학적 조성물. The pharmaceutical composition for preventing or treating ischemic brain disease of claim 1, wherein the composition is an oral or injectable preparation.
  7. 제1항에 있어서, 상기 피마살탄을 1mg 내지 240mg 포함하는, 허혈성 뇌질환 예방 또는 치료용 약학적 조성물. The pharmaceutical composition for preventing or treating ischemic brain disease according to claim 1, comprising 1 mg to 240 mg of fimasartan.
  8. 허혈성 뇌질환 예방 또는 치료를 위한 피마살탄(Fimasartan) 또는 그의 염의 용도. Use of Fimasartan or a salt thereof for preventing or treating ischemic brain disease.
  9. 피마살탄(Fimasartan) 또는 그의 염을 포함하는 조성물을 투여하여 허혈성 뇌질환을 예방 또는 치료하는 방법. A method for preventing or treating ischemic brain disease by administering a composition comprising Fimasartan or a salt thereof.
  10. 허혈성 뇌질환 예방 또는 치료용 약제의 제조를 위한 피마살탄(Fimasartan) 또는 그의 염의 사용. Use of Fimasartan or a salt thereof for the manufacture of a medicament for the prevention or treatment of ischemic brain disease.
PCT/KR2014/009296 2013-10-04 2014-10-02 Pharmaceutical composition for preventing or treating ischemic brain disorders, containing fimasartan WO2015050388A1 (en)

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